Pathological jaundice (here used as a synonym for cholestasis) is the most frequent presenting syndrome in children and adults with liver disease. It results from the impaired excretion of bile from the liver, with a range of underlying causes including genetic, metabolic, inflammatory, and drug- or toxin-induced disorders. Therefore, physicians are challenged to identify the cause of jaundice in order to initiate specific treatment and supportive measures to prevent progression and/or complications of liver disease. The prognosis and treatment course for these cholestasis related syndromes differ widely. Thus, identifying the precise cause of cholestasis or jaundice allows appropriate treatment to be provided to a patient exhibiting cholestasis.
Progressive familial intrahepatic cholestasis (PFIC), benign recurring intrahepatic cholestasis (BRIC), alpha1-antitrypsin deficiency, and Alagille disease constitute approximately 45% of neonatal jaundice cases. These diseases can be difficult to clinically define. The number and size of the cholestasis related genes underlying PFIC, BRIC, alpha1-antitrypsin deficiency, and Alagille disease has impaired the use of mutation detection as a diagnostic criterion. Cholestasis related genes underlying PFIC, BRIC, alpha1-antitrypsin deficiency, and Alagille disease include, but are not limited to, ATP8B1 (SEQ ID NO:71), ABCB11 (SEQ ID NO:72), ABCB4 (SEQ ID NO:73), JAG1 (SEQ ID NO:74), and SERPINA1 (SEQ ID NO:75). ATP8B1 is located on the long arm of chromosome 18 at 18q21.31. ABCB11 is located on the long arm of chromosome 2 at 2q24. ABCB4 is located on the long arm of chromosome 7 at 7q21.1. JAG1 is located on the short arm of chromosome 20 at 20p12.1-p11.23. SERPINA1 is located on the long arm of chromosome 14 at 14q32.1.
Development of efficient, accurate, sensitive methods of detecting mutations in the genes associated with cholestasis, particularly PFIC, BRIC, alpha1-antitrypsin deficiency, and Alagille syndrome is desirable. It is of importance to develop a method of predicting disease outcome with respect to treatment course. It is of particular importance to develop a method of determining cholestasis classification that would identify subjects likely to benefit from early aggressive treatment.